Endohedral metallofullerene contrast agents

ABSTRACT

An image contrast agent for creating an image of a portion of a body is disclosed. The contrast agent can provide contrast for two different types of imaging techniques, such as x-ray imaging and magnetic resonance imaging. The contrast agent includes an endohedral metallofullerene compound with an atom encapsulated in the fullerene cage for imaging based on one type of technique, and a second atom encapsulated in the fullerene cage for imaging based on a second type of technique. Alternatively, the contrast agent may include a first endohedral metallofullerene compound having a one type of contrast imaging characteristics, and a second endohedral metallofullerene compound having a second type of contrast imaging characteristics.

FIELD OF THE INVENTION

The present invention relates to contrast agents for use in imaging abody. More particularly, the present invention relates to contrastagents that provide for different types of imaging using endohedralmetallofullerene compounds.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 6,303,760, herein incorporated by reference in itsentirety, describes a family of endohedral metallofullerenes where atrimetallic nitride is encapsulated in a fullerene cage. The endohedralmetallofullerenes have the general formula A_(3-n)X_(n)N@Cm (n=0-3)where A is a metal, X is a second trivalent metal, n is an integer from0 to 3, and m is an even integer from about 60 to about 200. The metalsA and X may be an element selected from the group consisting of a rareearth element and a group IIIB element and may be the same or different.These trimetallic nitride endohedral metallofullerenes are produced byintroducing nitrogen gas into a Krätschmer-Huffman generator duringvaporization of packed graphite rods containing corresponding metaloxides, known as the trimetallic nitride template (TNT) process.

SUMMARY OF THE INVENTION

The present invention includes a contrast agent based on a trimetallicnitride endohedral metallofullerene compound having a first atom with afirst imaging contrast property and a second atom with a second imagingcontrast property, wherein the first atom and the second atom areencapsulated within the fullerene cage of the endohedralmetallofullerene.

The present invention also includes a contrast agent having the formulaLu₃N@C_(m) where m is an even integer from about 60 to about 200.

Still further, the invention includes a contrast agent that includes atrimetallic nitride endohedral metallofullerene compound having a firstatom with a first imaging contrast property encapsulated within afullerene cage of the endohedral metallofullerene, and a secondtrimetallic nitride endohedral metallofullerene compound having a secondatom with a second imaging contrast property encapsulated within afullerene cage of the endohedral metallofullerene.

The present invention also includes a contrast imaging method. Themethod includes administering an effective amount of a contrast agent toa subject, where the contrast agent comprises a trimetallic endohedralmetallofullerene compound having a first atom with an imaging contrastproperty encapsulated in the fullerene cage of the endohedralmetallofullerene. The method also includes applying an imaging techniqueto the subject, wherein the imaging technique provides an image of aportion of a subject based on the imaging contrast property of theadministered contrast agent.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

Contrast agents are used to absorb radiation and provide an imagingcontrast of the human anatomy. These contrast agents typically containatoms with high atomic numbers and their dense electronic environmentabsorbs X-ray radiation. Some common atoms used in contrast agentsinclude iodine, boron, and barium. To produce a better contrast, it isdesirable to use heavier elements. A difficulty is that many of theheavier elements that would be useful as a contrast agent may be toxicto the human body. Further, it would be useful to provide a singlecontrast agent that allows for the multiple imaging techniques, such asx-ray imaging and magnetic resonance imaging.

The present invention is directed to family of contrast agents thatprovide for the imaging of a subject using different imaging techniques.The contrast agents of the present invention allow for more than oneimaging technique to be used based on a single contrast agent. Forexample, and as will be discussed in detail below, one contrast agentcan be used to create both an x-ray image and a magnetic resonanceimage.

In a accordance with an embodiment of the present invention, a contrastagent includes a trimetallic nitride endohedral metallofullerenecompound having a first atom with a first imaging contrast property anda second atom with a second imaging contrast property encapsulatedwithin the fullerene cage of the endohedral metallofullerene.

The imaging contrast properties for the atoms in the contrast agentinclude, but are not limited to, x-ray imaging properties useful forx-ray imaging and computerized axial tomography (CAT) imaging, andmagnetic resonance imaging (MRI) properties useful for magneticresonance imaging. Elements useful for the first and second atomsinclude rare earth and group IIIB elements. Preferably, the first atomand second atoms may each be selected from the group consisting oflutetium, yttrium, erbium, europium, holmium, gadolinium, terbium,dysprosium, and depleted uranium. All of these elements would be usefulin x-ray imaging techniques. Elements useful for magnetic resonanceimaging are preferably lutetium, gadolinium, terbium, dysprosium,holmium, and erbium. In certain embodiments, the first and second atomsshould provide different imaging properties. In further embodiments, thefirst and second atoms may be the same provided that they provide foruse in different imaging techniques. For example, lutetium may be usedfor x-ray imaging as well as magnetic resonance imaging. In this case,lutetium may be used for the first and second atoms.

In certain embodiments lutetium may be used as the first atom, and thesecond atom may be selected from the group consisting of lutetium,yttrium, erbium, europium, holmium, gadolinium, terbium, dysprosium, anddepleted uranium.

Any fullerene cage known to one of skill in the art may be used toencapsulate the atoms. Preferably, the fullerene cages include, but arenot limited to a C₆₈ cage, C₇₈ cage, and C₈₀ cage. A preferredembodiment utilizes a C₈₀ fullerene cage.

The trimetallic nitride endohedral metallofullerene compound may havethe formula A_(3-n)X_(n)N@C_(m), where A is the first atom having afirst imaging contrast property and X is the second atom having a secondimaging contrast property, n can range from 0 to 3, and m can range fromabout 60 to about 200. The first atoms and second atoms have the samecriteria as that discussed above. Certain embodiments for the contrastagent include, but are not limited to, Lu₃N@C₈₀, Gd₂LuN@C₈₀, GdLu₂N@C₈₀,ErLu₂N@C₈₀, Er₂LuN@C₈₀, HoLu₂N@C₈₀, and Ho₂LuN@C₈₀.

As used herein, “endohedral” refers to the encapsulation of atoms insidea fullerene cage network. Accepted symbols for elements and subscriptsto denote numbers of elements are used herein. Further, all elements tothe right of an @ symbol are associated with the exterior of thefullerene cage network, while all elements listed to the left arecontained within the fullerene cage network. Under this notation,Lu₃N@C₈₀ indicates that the Lu₃N trimetallic nitride is situated withina C₈₀ fullerene cage.

The embodiments discussed above are directed to a single endohedralmetallofullerene having two different types of imaging properties. Anaccordance with another embodiment of the present invention, a contrastagent may include a mixture of endohedral metallofullerene compounds,where different endohedral metallofullerene compounds provide fordifferent imaging properties. For example, an embodiment of the presentinvention includes a trimetallic nitride endohedral metallofullerenecompound having a first atom with a first imaging contrast propertyencapsulated within a fullerene cage of the endohedral metallofullerene,and a second trimetallic nitride endohedral metallofullerene compoundhaving a second atom with a second imaging contrast propertyencapsulated within a fullerene cage of the endohedral metallofullerene.The first atom and second atom have the same characteristics and imagingproperties, and include the same elements as those discussed above.Likewise the fullerene cage includes the fullerene cages discussedabove.

The trimetallic nitride endohedral metallofullerene compounds used inthe contrast agent can also be functionalized on the exterior of thefullerene cage (“exohedral”). U.S. patent application Ser. No.10/244,747, entitled “Endohedral Metallofullerene Derivatives,” hereinincorporated by reference in its entirety describes thefunctionalization of endohedral metallofullerenes. The functionalizationallows for changes in solubility in different solvent systems. Theendohedral metallofullerene can be made more hydrophobic or hydrophilicdepending on the functional group added to the exterior of the fullerenecage. Exohedral functionalization of the carbon cage can provide forimproved bio-distribution. This functionalization involves one or moreappendage groups attached to the carbon cage. Functionalizing theendohedral metallofullerenes can take place by various reactions,including, but not limited to, hydroxylation, Diels-Alder reactions,Bingel-Hirsch reaction, and other similar reaction mechanisms.

The present invention also includes a contrast imaging method. Themethod includes administering an effective amount of a contrast agent toa subject, wherein the contrast agent comprises a trimetallic endohedralmetallofullerene compound having a first atom with an imaging contrastproperty encapsulated in the fullerene cage of the endohedralmetallofullerene, and applying an imaging technique to the subject. Theimaging technique provides an image of a portion of a subject based onthe imaging contrast property of the administered contrast agent. Thefirst atom, second atom, and fullerene cage may include thecharacteristics discussed above with respect to the embodiments for thecontrast agent.

The method also includes a contrast agent that includes a second atomhaving a second imaging contrast property. The second atom may beencapsulated in the fullerene cage with the first atom or as part of asecond endohedral metallofullerene compound as discussed above.

The effective amount of a contrast agent will vary depending on thesubject and the specific contrast agent being used and requires anamount to form a image based on the technique being used. The imagingtechniques may include, but are not limited to, x-ray imaging,computerized axial tomography, or magnetic resonance imaging.

Once the contrast agent is administered to the subject, the contrastingagent moves through the body. After a sufficient amount of time, thedesired imaging technique is performed. The method of applying thedesired imaging technique will vary depending the imaging technique andare well known by those skilled in the art.

By encapsulating the high atomic number metal atom within a carbonstructure, the high atomic number metal atom cannot readily escape thestructure; thus reducing the potential for toxic exposure of the highatomic number metal atom to a human. Further, by providing differentimaging contrast properties in the same contrast agent, differentimaging techniques can be performed on the subject with have to providethe subject with a separate and different agent.

While the invention has been described in terms of its preferredembodiments, those skilled in the art will recognize that the inventioncan be practiced with modification within the spirit and scope of theappended claims.

1. A contrast agent, comprising: a trimetallic nitride endohedralmetallofullerene compound having a first atom with a first imagingcontrast property and a second atom with a second imaging contrastproperty, wherein the first atom and the second atom are encapsulatedwithin the fullerene cage of the endohedral metallofullerene.
 2. Thecontrast agent of claim 1, wherein the first imaging contrast propertyand the second imaging contrast property are different.
 3. The contrastagent of claim 1, wherein the first atom is lutetium.
 4. The contrastagent of claim 1, wherein the first atom is lutetium and the second atomis a rare earth or group IIIB element.
 5. The contrast agent of claim 1,wherein the first atom is lutetium and the second atom is yttrium,erbium, europium, holmium, gadolinium, terbium, dysprosium, or depleteduranium.
 6. The contrast agent of claim 1, wherein the first atom islutetium, yttrium, erbium, europium, holmium, gadolinium, terbium,dysprosium, or depleted uranium; and wherein the second atom islutetium, yttrium, erbium, europium, holmium, gadolinium, terbium,dysprosium, or depleted uranium.
 7. The contrast agent of claim 1,wherein the first imaging contrast property is an x-ray absorptionproperty for use in forming an image, and wherein the second imagingcontrast property is a magnetic resonance imaging property.
 8. Thecontrast agent of claim 1, wherein the fullerene cage is C₆₈, C₇₉, orC₈₀.
 9. The contrast agent of claim 1, wherein the fullerene cage isC₈₀.
 10. A contrast agent, comprising a compound having the formula:Lu₃N@C_(m) wherein m is an even integer from about 60 to about
 200. 11.A contrast agent, comprising: a trimetallic nitride endohedralmetallofullerene compound having a first atom with a first imagingcontrast property encapsulated within a fullerene cage of the endohedralmetallofullerene; and a second trimetallic nitride endohedralmetallofullerene compound having a second atom with a second imagingcontrast property encapsulated within a fullerene cage of the endohedralmetallofullerene.
 12. The contrast agent of claim 11, wherein the firstimaging contrast property and the second imaging contrast property aredifferent.
 13. The contrast agent of claim 11, wherein the first atom islutetium.
 14. The contrast agent of claim 11, wherein the first atom islutetium and the second atom is a rare earth or group IIIB element. 15.The contrast agent of claim 11, wherein the first atom is lutetium andthe second atom is yttrium, erbium, europium, holmium, gadolinium,terbium, dysprosium, or depleted uranium.
 16. The contrast agent ofclaim 11, wherein the first atom is lutetium, yttrium, erbium, europium,holmium, gadolinium, terbium, dysprosium, or depleted uranium; andwherein the second atom is lutetium, yttrium, erbium, europium, holmium,gadolinium, terbium, dysprosium, or depleted uranium.
 17. The contrastagent of claim 11, wherein the first imaging contrast property is anx-ray absorption property for use in forming an image, and wherein andthe second imaging contrast property is a magnetic resonance imagingproperty.
 18. The contrast agent of claim 11, wherein the fullerene cageis C₆₈, C₇₈, or C₈₀.
 19. The contrast agent of claim 11, wherein thefullerene cage is C₈₀.
 20. A contrast imaging method, comprising thesteps of: administering an effective amount of a contrast agent to asubject, wherein the contrast agent comprises a trimetallic endohedralmetallofullerene compound having a first atom with an imaging contrastproperty encapsulated in the fullerene cage of the endohedralmetallofullerene; and applying an imaging technique to the subject,wherein the imaging technique provides an image of a portion of asubject based on the imaging contrast property of the administeredcontrast agent.
 21. The method of claim 20, wherein the imagingtechnique X-ray imaging, computerized axial tomography, or magneticresonance imaging.
 22. The method of claim 20, wherein the contrastagent further comprises: a second atom with a second imaging contrastproperty, wherein the first atom and the second atom are encapsulatedwithin the fullerene cage of the endohedral metallofullerene.
 23. Themethod of claim 22, wherein the first imaging contrast property and thesecond imaging contrast property are different.
 24. The method of claim20, wherein the first atom is lutetium.
 25. The method of claim 22,wherein the first atom is lutetium and the second atom is a rare earthor group IIIB element.
 26. The method of claim 22, wherein the firstatom is lutetium and the second atom is yttrium, erbium, europium,holmium, gadolinium, terbium, dysprosium, or depleted uranium.
 27. Themethod of claim 22, wherein the first atom is lutetium, yttrium, erbium,europium, holmium, gadolinium, terbium, dysprosium, or depleted uranium;and wherein the second atom is lutetium, yttrium, erbium, europium,holmium, gadolinium, terbium, dysprosium, or depleted uranium.
 28. Themethod of claim 22, wherein the first imaging contrast property is anx-ray absorption property for use in forming an image, and wherein andthe second imaging contrast property is a magnetic resonance imagingproperty.
 29. The method of claim 20, wherein the contrast agent furthercomprises: a second trimetallic nitride endohedral metallofullerenecompound having a second atom with a second imaging contrast propertyencapsulated within a fullerene cage of the endohedral metallofullerene.30. The method of claim 29, wherein the first imaging contrast propertyand the second imaging contrast property are different.
 31. The methodof claim 29, wherein the first atom is lutetium, yttrium, erbium,europium, holmium, gadolinium, terbium, dysprosium, or depleted uranium;and wherein the second atom is lutetium, yttrium, erbium, europium,holmium, gadolinium, terbium, dysprosium, or depleted uranium.
 32. Themethod of claim 29, wherein the first imaging contrast property is anx-ray absorption property for use in forming an image, and wherein andthe second imaging contrast property is a magnetic resonance imagingproperty.